The qualitative and quantitative acquisition of morphological, functional and biochemical parameters using imaging methods is the basis for a plurality of medical research and application areas. An overview over known imaging methods is given in “Scaling down imaging: Molecular mapping of cancer in mice”, R. Weissleder, Nat Rev Cancer (1/2002), Volume 2, 1-8. Known imaging methods, which are applied e.g. in tumor research, include optical imaging techniques.
Such imaging methods for in-vivo examination known in the state-of-the-art are optical imaging techniques including fluorescence or bioluminescence imaging. In fluorescence imaging, light of one excitation wavelength illuminates the imaged object, resulting in a shifted emission wavelength that can be collected by a photo detector such as a CCD-camera. The imaged object is labelled for this purpose using a variety of fluorescence probes. Smart probes have been developed, that can be activated and detected only when they interact with a certain target, e.g. a small molecule, peptide, enzyme substrate or antibody. Bioluminescence imaging is used to detect photons that are emitted from cells that have been genetically engineered to express luciferases, catalysts in a light generating reaction, through the oxidation of an enzyme-specific substrate (luciferin). Unlike fluorescence approaches, the imaged object does not need to be exposed to the light of an external light source, the technique being based upon the internal light produced by the luciferases.
Planar optical imaging and optical tomography (OT) are emerging as alternative molecular imaging modalities, that detect light propagated through tissue at single or multiple projections. A number of optical-based imaging techniques are available, from macroscopic fluorescence reflectance imaging to fluorescence imaging/tomography that has recently demonstrated to localize and quantify fluorescent probes in deep tissues at high sensitivities at millimeter resolutions. In the near future, optical tomography techniques are expected to improve considerably in spatial resolution by employing higher-density measurements and advanced photon technologies, e.g. based upon modulated intensity light or very short photon pulses. Clinical optical imaging applications will require high efficient photon collection systems. OT has recently found applications, such as imaging of breast cancer, brain function and gene expression in vivo. Primary interest for using optical imaging techniques lies in the non-invasive and non-hazardous nature of optical photons used, and most significantly in the availability of activateable probes that produce a signal only when they interact with their targets—as compared to radiolabelled probes which produce a signal continuously, independent of interacting with their targets, through the decay of the radioisotope. In OT, images are influenced greatly by the spatially dependent absorption and scattering properties of tissue. Boundary measurements from one or several sources and detectors are used to recover the unknown parameters from a transport model described, for instance, by a partial differential equation. The contrast between the properties of diseased and healthy tissue can be used in clinical diagnosis.
In the state of the art optical imaging detectors are known either with (non-contact) CCD based or with (contact) fibre-optics based optical imaging designs.
The majority of existing optical imaging approaches are CCD based. CCDs (charge coupled devices) are charge coupled imaging sensors that serve for highly sensitive detection of photons. The CCD camera is divided into a multiplicity of small light-sensitive zones (pixels) which produce the individual points of an image. The grid of the pixels is formed by a circuit structure on a semiconductor crystal (usually silicon). The method of operation of the CCD camera is based on the liberation of electrons by impinging light in the semiconductor material. A photon falling onto a pixel liberates at least one electron that is held fixed by an electrical potential at the location of the pixel. The number of electrons liberated at the location of the pixel is proportional to the intensity of the light incident at that location. The number of electrons is measured in each pixel, with the result that an image can be reconstructed. CCDs should be cooled since otherwise more electrons would be read out which would not be liberated as a result of the light incidence but rather as a result of heating. In order to define an optical field-of view, the CCD detector is typically coupled to a lens.
However, almost all of the commercially available CCD based imaging designs generate only planar images of the integrated light distribution emitted from the surface of the imaged object, e.g. an animal. Market leader in the small animal optical imaging instrumentation arena is Xenogen Corp. Alameda, USA. The principle design of known CCD based optical imaging systems as used for in vivo fluorescence and bioluminescence imaging comprises a CCD camera, which is arranged at a certain distance to the imaged object (non-contact measurement) and aimed at this object in order to detect photons emitted from the object. Since CCD detectors need to be equipped with a lens which does impose a minimal focal length CCD cameras tend to be rather bulky instruments yielding large imaging compartments. If eventually used for tomographic imaging a CCD-based camera system needs to be rotated around the imaged object in order to collect projection views or a multitude of cameras needs to be used in parallel. In another potential application lens-based CCD camera systems of the prior art cannot be positioned within the field-of-view of another imaging modality with the purpose of dual-modality image acquisition such as positron emission tomography (PET) for simultaneous PET/optical imaging.
Known fibre optics based optical imaging designs are being used in a way that the fibre ending tips are placed in contact with the object to be imaged. One of the reasons is that a particular fibre ending tip does not have a distinct well-defined field of view which would allow for backtracking a photon's incoming direction. That means, for non-cylindrical imaging objects, such a mice, the object needs to be put into a cylindrical compartment which is filled with an appropriate liquid having specific optical properties. This is considered a significant drawback because of animal handling issues, experimental complexity and study management.